Presidential perspectives Professor Sir John Bell talks to Geoff Watts about medical science – from the recent past to the near future As part of the Academy of Medical Sciences’ 10th anniversary celebrations, we asked Dr Geoff Watts FMedSci to conduct a series of interviews with the President, Professor Sir John Bell FRS PMedSci. The broad theme was‘medical science, from the recent past to the near future’. Captured here are some highlights from the interviews, giving Sir John’s perspectives on molecular medicine, stem cells and diseases of the developed and developing world, as well as the role of the Academy. Molecular medicine principal research interests lie within one of the topics set to change the way medicine operates: ‘The rapid advances in human molecular the molecular basis of disease. So a good place genetics seen over the past five years indicate to begin this skim through some of his thinking. that within the next decade genetic testing will be used widely for predictive testing in healthy ‘I think there’s a rule that big people and for diagnosis and management of discoveries in biomedicine take at patients.’ – John Bell. BMJ (1998) 316, 618. least 20 years to impact in the clinic.‘ Making predictions on the record is risky - but Professor Sir John Bell has the self-assurance to That he sees the sequencing of the human offer an occasional hostage to fortune. As the genome as a scientific milestone comes as no date on the quote above from the BMJ reveals, surprise. But a clinical one as well?‘I think there’s not every prediction hits all the bull’s-eyes dead a rule that big discoveries in biomedicine take centre. So does he now recoil from his 1998 at least 20 years to impact in the clinic. vision of the future of molecular genetics? Not Monoclonal antibodies are an example. They at all; his confidence in the science and its were invented in the early seventies, but the first relevance to clinical medicine is undiminished. therapeutic antibodies appeared in the mid- nineties.‘ ‘I got the time frame wrong. But I think most people would now accept that this [the impact ‘You have to take the human genome in that of molecular genetics] is real – and will become context. Genetics and genetic manipulation more real. It’s very difficult to see how we can really emerged in the mid seventies when we continue the same paradigm of health care with learned how to stick two pieces of DNA its dramatically rising costs and the relatively together. They started to impact on drug inefficient application of costly new therapies discovery and the identification of new targets across large populations when they give only by the mid to late eighties. But the sequencing modest benefits. In fact we know that if you can of the genome and an understanding of the find the population in which those therapies variation within it only came in the early to mid work really well, efficacy rises dramatically.’ nineties. We’re now beginning to see the first tests having wide applications in diagnostics. The Presidency of the Academy of Medical But it’s an exciting initial step.’ Sciences is an office carrying many obligations including, inevitably, an expectation that its In short, Bell has no doubt that the human holder will have informed opinions on genome project will change medicine radically. everything. This is hardly possible; but two hours Recalling his 1998 BMJ article he laughs,‘It’s one of wide-ranging discussion suggest that Bell of my most cited papers because most people knows what he thinks about the past hated it. They didn’t believe it would happen. developments that have shaped the medicine The charge was lead by some people in the we have today, and about the current research genetics community who were used to dealing which is even now creating its future. His own with highly penetrant single gene disorders and didn’t believe we’d ever be able to make sense information…well, I think that works.’ of the big complex traits.’ The idea that Twenty years ago only a handful of known gene cardiologists and oncologists and variants had been associated with a rheumatologists would all be using these tools predisposition to common disease. By the to make decisions about their patients was not, beginning of this year, says Bell, there were 130. it seems, one that roused initial enthusiasm. By the end of it there will be over 200 and, by the end of next year, 400.‘None of those original One of the doubts sometimes voiced about the 130 would have been on anyone’s list of personalised medicine made possible by the candidate genes that might cause disease. So genome project is that this customised the concept of hypothesis-driven biomedical approach will prove prohibitively expensive, science that’s shaped the research agenda has with increasing numbers of drugs being got some holes in it. You’ve got to be very produced for ever smaller groups of patients. careful not to be too confident about what you Bell sees the concern, but reckons that if it does know, because chances are it’s wrong!’ prove to be a problem, it’s still a long way off. On the time scale of which he’s thinking, clinicians A wish would be using predisposition genes, the expression levels of certain genes, epigenetic Asked to pick just one medical achievement that markers and a variety of other ways to identify would give him the greatest satisfaction, he sub-groups of perhaps 10 or 20 per cent of a singles out the avoidance of premature death in population of patients with a particular disorder. young middle-aged people.‘Serious disease ‘If you take a drug which, in a large randomised afflicting anyone aged 35 to 40 is a complete trial, gives you efficacy in say only 30 per cent, nightmare. It destroys family units and it’s but you then identify those 30 per cent and disruptive from a societal point of view. Although treat only them, your efficacy rises dramatically.’ the numbers are fairly small, the impact is And it’s good for the pharmaceutical companies. disproportionately great. The deaths are mostly ‘They’ll penetrate the market much more due to vascular disease and cancer.’ And there is, effectively. In that 30 per cent, everyone’s going of course, no single or simple remedy. to want the drug.’ Cost in the longer term, if the‘personalisation’ enterprise does make inroads, is hard to judge. Stem cells But Bell remains optimistic. He quotes the example of people who develop a severe The topic of the moment in biomedicine - at least myopathy in response to treatment with statins. as measured by the media coverage - is the One genetic variant accounts for the vast creation and use of embryonic stem cells. Here too majority of cases.‘The tools to find the genetic Bell applies his 20 year rule of thumb, but he variants that cause those rare adverse reactions worries about the distracting effect of arguments are increasingly available. Provided it’s part of an between supporters of adult versus embryonic integrated system in which you pay once for a cells. ‘The hum and buzz associated with the use DNA chip giving you a broad range of of human embryonic cells is understandable, but the opportunities associated with adult stem cells ‘The concept of hypothesis-driven should not be missed. Mesenchymal cells from biomedical science that’s shaped the bone marrow that can be differentiated into research agenda has got some holes in cartilage and fibrous tissues for use in orthopaedics look pretty interesting to me. And I it. You’ve got to be very careful not to be think there will be other examples.’ too confident about what you know, because chances are it’s wrong!’ ‘The fact is we need research across several arenas - adult (including reprogrammed cells), of what the rest of China can anticipate, says fetal and embryonic stem cells. The research is Bell, the scale of the problem that awaits is truly complementary – at present, we don’t know vast. ‘There is an opportunity to recognise that which route will ultimately be most effective, this is coming and do something. But this hasn’t and closing off any one avenue of research been properly discussed at a policy level, could be detrimental.’ nationally or internationally, and it’s going to He stresses the importance of ongoing dialogue ‘HIV, malaria and diarrhoeal diseases between scientists, policymakers and the public on stem cells and other issues. ‘The Academy’s will continue to wreak havoc among report in 2007 on inter-species embryos was an the billion poorest people on the important platform to explain the science calmly planet, but we’ve also got to keep our and objectively and to promote consistency around terminology. It is this dialogue that has eye on this other epidemic of diabetes.’ resulted in a Human Fertilisation and Embryology Bill that commands wide support create a huge burden for health systems.’ and that will keep the UK at the forefront of stem The policy decisions that need to be taken cell science.’ involve economics, education, changes to the way we live, and much else. ‘The World Health On planning research Organisation is very good at managing infectious disease problems, but has yet to seize on chronic In planning a programme of future research Bell diseases in a serious way. It spends only about 2-3 likes to talk of‘placing bets’: of backing what you per cent of the budget on them.